Protease inhibitors (PIs) offer many patients long-term survival without acute complications of AIDS. A common syndrome of subcutaneous fat wasting, visceral fat accumulation, hypertriglyceridemia, accelerated atherosclerosis and insulin resistance has been identified recently in HIV-infected patients receiving PI therapy. The potential morbidity and mortality associated with this syndrome has raised concerns about the long-term safety of PI therapy. The goal of this project is to define the defects in lipid and carbohydrate metabolism that underlie this syndrome in carefully selected patients. We hypothesize that PIs incduce insulin resistance, resulting in impaired glucose utilization and increased basal lipolysis. the increased lipolysis, together with defective fatty acid reesterification and triglyceride utilization, result in lipopdystrophy and visceral fat accumulation. We propose to study 7 HIV+ subjects on PI therapy and clinically manifesting the lipodystrophic syndrome, and 7 age-, sex-ethnic group-matched HIV+ control subjects prior to and 6 months following initiation of PI therapy, with the following specific aims: 1) To quantify whole body insulin resistance using a modified minimal model intravenous glucose tolerance test with a labeled glucose tracer; 2)to measure the post-absorptive rates of lipolysis, fatty acid reesterification and triglyceride utilization using stable isotope/mass spectrometry protocols with labeled glycerol, palmitate and tripalmitin tracers. the heterogeneity of the PI-associated metabolic syndrome suggest that it represents a complex phenotype. Our long-term goal is to define the syndrome comprehensively, using tools that are able to quantify simultaneously multiple intersecting pathways that regulate intermediary metabolism and body composition. We have therefore assembled the combined expertise of HIV clinical specialists, endocrinologists experienced in human metabolic protocols, and biochemists with substantial expertise in stabel isotope techniques to investigate complex aspects of fuel metabolism. he present pilot study will lead to a more comprehensive, longitudinal study of altered metabolism associated with antiretroviral therapy, and ultimately to rational approaches aimed at decreasing the metabolic risks to patients receiving such therapy.